Radiopharmaceutical compounds have been in use for diagnostic purposes for many years and one skilled in the art of nuclear medicine and radiopharmaceutical research is well aware of the requirements for a diagnostically useful radiopharmaceutical. Briefly, these requirements include: efficient preparation of the radiopharmaceutical, such that preparation in the hospital or pharmacy is possible; efficient transport of the radiopharmaceutical to the target organ; efficient extraction of the radiopharmaceutical by the target organ, such that adequate target to background ratios are achieved to allow diagnostic distinctions; adequate retention in the target organ to allow detection using conventionally available radiation monitoring equipment.
Diaminedithiol complexes of technetium-99m as radiopharmaceuticals have been described previously. Both Burns et al. in European Patent Application 163,119, published Dec. 4, 1985, and Kung et al. in European Patent Application 200,211, published Nov. 5, 1986, describe the use of amine derivatized diaminedithiol complexes of technetium-99m as radiopharmaceuticals useful for determining regional cerebral blood flow. While these complexes have been shown to exhibit adequate uptake into the brains of mammals to provide good target to background ratios, these compounds have shown rather rapid washout from the brain tissue, restricting their usefulness for single photon emission computed tomography with conventionally available equipment.
Lin, U.S. Pat. No. 4,284,619 issued Aug. 18, 1981 describes the use of esters as brain imaging agents. Specifically described are esters of iodinated benzoic acids. These compounds showed very poor brain retention, with the brain to blood ratio at 5 minutes being less than 0.5 in all cases.
Davison et al. in European Patent Appln. No. 135,160, published Mar. 27, 1985, describe the use of a variety of substituted diamidedithiol complexes of technetium-99m as renal imaging agents. These diamidedithiol ligands result in the formation of anionic complexes with technetium, resulting in high renal extraction, but the anionic charge on these complexes appears to eliminate the potential for adequate brain extraction. Similar anionic complexes are described by Fritzberg, U.S. Pat. No. 4,444,690 issued Apr. 24, 1984; and by Byrne et al., U.S. Pat. No. 4.434,151 issued Feb. 28, 1984; U.S. Pat. No. 4,571,430 issued Feb. 18. 1986; and U.S. Pat. No. 4.575,556 issued Mar. 11, 1986.
Troutner et al. in European Patent Appln. No. 123,504, published Oct. 31, 1984, describe neutral technetium-99m complexes with alkylene amine oximes and their use as radiopharmaceuticals for the evaluation of regional cerebral blood flow. While these compounds have shown adequate brain extraction as well as prolonged retention in the brain of mammals, these complexes convert on standing to a hydrophilic complex which is no longer effective as a radiopharmaceutical for evaluation of regional cerebral blood flow. This conversion with time requires that the radiopharmaceutical be used within 30 minutes after preparation.
Clearly the need exists for more effective radiopharmaceuticals for the evaluation of regional cerebral blood flow which will combine the necessary properties of adequate brain uptake, adequate retention within the brain. distribution in accordance to blood flow, and adequate stability after preparation to be useful in the clinical environment.
U.S. Pat. No. 2,810,753 issued Oct. 22, 1957, describes di-sulfhydryl alkylene diamine polycarboxylic acids as metal ion chelating agent. Some of these acids are immediate precursors to the ester-substituted diaminedithiols of the present invention.
Blondeau et al., Can. J. Chem., 45, 49 (1967). describe the reductive dimerization of thiazolidines to yield N,N'-1,2-ethylenediylbis-L-cysteine derivatives.
A copper complex of N,N'-1,2-ethylenediylbis-L-cysteine, dimethyl ester prepared from the dimethylester dihydrochloride is characterized by Bharadwaj et al., J. Am. Chem. Soc., 108, 1351 (1986).